1. Field of the Invention
The present invention relates to benzoquinones, their use as antihyperlipidemic agents, a process for their preparation, and pharmaceutical compositions.
2. Description of the Art
It is generally recognized that high blood cholesterol levels are a significant risk factors in cardiovascular disease.
It has been established that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the first rate limiting enzyme in the biosynthetic pathway for cholesterol, that inhibition of HMGR activity results in a decrease in serum total cholesterol and low density lipoprotein (LDL) cholesterol levels, and that a decrease in serum LDL-cholesterol levels is reflected in a reduction of plasma level of apolipoprotein B. (Brown, et al, J. Lipid Res. 21: 505-517 (1980)).
Tocotrienols have been shown to suppress HMGR resulting in the inhibition of cholesterol biosynthesis and a subsequent drop in LDL cholesterol, apolipoprotein B, thromboxane B.sub.2, platelet factor 4 and glucose levels. (Wright, et al. A Symposium On Drugs Affecting Lipid Metabolism, Houston, Tex. (November 1989)).
Idebenone (Formula I) is marketed in Japan (Takeda-AVAN 1986) for age-related cerebrovascular disorders of the brain. ##STR1##
Pharmacokinetic studies with Idebenone in man have shown that the drug is absorbed rapidly and has somewhat poor (15-30%) bioavailability due to low intestinal absorption. Idebenone lacks the farnesylated side chain and would not be expected to exhibit hypocholesterolemic activity.
The ubiquinones, also known as Coenzymes Q, are a group of benzoquinones involved in electron transport mechanisms within mitochondria. The most common ubiquinone in mammalian systems is ubiquinone-10 (n=10, Formula II). The plastoquinones (Formula III) are found predominately in the chloroplasts of higher plants and play a similar role to the ubiquinones by acting as a redox carrier in the electron transport system. (Boehme, H., et al., Z. Naturforsch., 26, 341-352 (1971)).
Vitamin K.sub.2, also known as the menaquinones, are antihemorrahagic vitamins wherein n is ususally between 7-9 (Formula IV). ##STR2##
Vitamin K.sub.2 (n=4) was examined in vivo and appears to actually elevate cholesterol levels [Table II, intra].
Ubiquinol inhibits lipid peroxidation in submitochondrial particles. (Forsmark, P., et al. FEBS Letters, 285: 39-43 (1991)). Recently, Stocker et al. (Stocker, et al., Proc. Natl. Acad. Sci. U.S.A., 88: 1646-1650, (1991)) have shown that ubiquinol-10 (the hydroquinone form of ubiquinone-10) is an inhibitor of LDL oxidation and is much more efficient than tocopherol in this respect. Packer et al. (Packer, et al., Res. Comm. Chem. Path. & Pharm., 72: 231-241 (1991)) have shown that ubiquinone has a sparing effect on tocopherol in rat liver microsomes and mitochondrial membranes, Littarru et al. (Littarru, et al., Drugs Exptl. Clin. Res., 8: 529-532 (1985)) have found that the ubiquinones are potent scavengers of superoxide. They indicated that preliminary evidence suggested that the reduced forms did not exhibit this activity.